Indole derivatives as 5HT1C antagonists

ABSTRACT

A compound of formula (I) or a salt thereof: ##STR1## Wherein: P represents a quinoline or isoquinoline residue; R 1  is hydrogen or C 1-6  alkyl; R 2 , R 3 , R 10 , R 11  are independently hydrogen 
     R 1  is hydrogen or C 1-6  alkyl; R 2 , R 3 , R 10 , R 11  are independently hydrogen or C 1-6  alkyl, or R 10  and R 11  together form a bond, or R 2  and R 10  or R 3  and R 11  together form a C 2-6  alkylene chain. R 4  is hydrogen, C 1-6  alkyl, halogen, NR 8  R 9 , OR 12  or COOR 12 , where R 8  R 9  and R 12  are independently hydrogen or C 1-6  alkyl; R 5  and R 6  are independently hydrogen or C 1-6  alkyl; and R 7  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indoline ring, which has been found to have 5HT 1c  receptor antagonist activity.

This application is the National Phase of PCT/GB93/00449 filed on Mar.4, 1993.

This invention relates to compounds having pharmacological activity, toa process for their preparation, to compositions containing them and totheir use in the treatment of mammals.

P. Fludzinski et al. J. Med. Chem. 1986 29 2415-2418 describesN-(1,2-dimethyl-3-ethyl-1H-indol-5-yl)-N'-(3-trifluoromethylphenyl)ureawhich shows selectivity for the rat stomach fundus seretonin receptor.

A class of compounds has now been discovered which have been found tohave 5HT_(1C) receptor antagonist activity. 5HT_(1C) receptorantagonists are believed to be of potential use in the treatment of CNSdisorders such as anxiety, depression, obsessive compulsive disorders,migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panicattacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine,and benzodiazepines, schizophrenia, and also disorders associated withspinal trauma and/or head injury, such as hydrocephalus.

Accordingly, the present invention provides a compound of formula (I) ora salt thereof: ##STR2## wherein: P represents a quinoline orisoquinoline residue or a 5- or 6-membered aromatic heterocyclic ringcontaining up to three heteroatoms selected from nitrogen, oxygen orsulphur;

R₁ is hydrogen or C₁₋₆ alkyl;

R₂, R₃, R₁₀ and R₁₁ are independently hydrogen or C₁₋₆ alkyl, or R₁₀ andR₁₁ together form a bond, or R₂ and R₁₀ or R₃ and R₁₁ together form aC₂₋₆ alkylene chain;

R₄ is hydrogen, C₁₋₆ alkyl, halogen, NR₈ R₉, OR₁₂ or COOR₁₂, where R₈,

R₉ and R₁₂ are independently hydrogen or C₁₋₆ alkyl;

R₅ and R₆ are independently hydrogen or C₁₋₆ alkyl; and

R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and wherein the ureamoiety is attached at the 4-, 5- or 6-position of the indole or indolinering, provided that P is not pyridyl when R₁₀ and R₁₁ form a bond.

Alkyl moieties within the variables R₁ to R₁₂ are preferably C₁₋₃ alkyl,such as methyl, ethyl, n- and iso-propyl, most preferably methyl.

Suitable R₄ and R₇ halogens include chloro and bromo.

Examples of R₁ include hydrogen, methyl, ethyl and n-propyl, preferablymethyl.

R₂ and R₃ are preferably hydrogen. R₁₀ and R₁₁ are preferably a bond soas to form an indole structure. In an indoline structure, R₁₀ and R₁₁are preferably hydrogen.

Preferably R₄ is hydrogen or methyl, most preferably hydrogen.

Preferably R₅, R₆ and R₇ are hydrogen.

The urea moiety can be attached to a carbon or nitrogen atom of the ringP, preferably it is attached to a carbon atom.

Suitable moieties when the ring P is a 5- or 6-membered aromaticheterocyclic ring include pyrazinyl, pyridazinyl, pyrimidinyl,isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. When P is aquinoline or isoquinoline residue, the urea moiety can be attached atany position of the ring, preferably to the 4-position.

The urea moiety is preferably attached at the 5-position of the indoleor indoline ring.

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonicacids.

Compounds of formula (I) may also form N-oxides or solvates such ashydrates, and the invention also extends to these forms. When referredto herein, it is understood that the term compound of formula (I) alsoincludes these forms.

When R₁ (in an indole) and/or R₅ and/or R₆ are hydrogen or when R₄ ishydroxy or NR₈ R₉ and at least one of R₈ and R₉ are hydrogen thecompounds of formula (I) may exist tautomerically in more than one form.The invention extends to these and any other tautomeric forms andmixtures thereof.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including enantiomers and the invention extends toeach of these stereoisomeric forms and to mixtures thereof includingracemates. The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) the coupling of a compound of formula (II); ##STR3## with a compoundof formula (III); ##STR4## wherein B is attached at the 4-, 5- or6-position of the indole or indoline ring and A and B contain theappropriate functional group(s) necessary to form the moiety --NR₅'CONR₆ '-- when coupled, wherein R₅ ' and R₆ ' are R₅ and R₆ as definedin formula (I) or groups convertible thereto, and the variables R₁ ', R₂', R₃ ', R₁₀ ', R₁₁ ', R₄ ' and R₇ ' are R₁, R₂, R₃, R₁₀, R₁₁, R₄ and R₇respectively, as defined in formula (I), or groups convertible thereto,and thereafter optionally and as necessary and in any appropriate order,converting any R₁ ', R₂ ', R₃ ', R₁₀ ', R₁₁ ', R₄ ', R₅ ', R₆ ' and R₇ 'when other than R₁, R₂ , R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇ respectively toR₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁, R₂, R₃,R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and forming a pharmaceutically acceptablesalt thereof; or

(b) cyclising a compound of formula (IV): ##STR5## wherein R₄ ', R₅ ',R₆ ' and R₇ ' are as defined in formulae (II) and (III) and C and Dcontain the appropriate functional group(s) necessary to form the indoleor indoline ring substituted by R₁ ', R₂ ', R₃ ', R₁₀ ', and R₁₁ ' asdefined in formula (III), and thereafter optionally and as necessary inany appropriate order, converting any R₁ ', R₂ ', R₃ ', R₁₀ ', R₁₁ ', R₄', R₅ ', R₆ ' and R₇ ' when other than R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆and R₇, to R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁,R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and optionally thereafter forming apharmaceutically acceptable salt.

Suitable examples of groups A and B include:

(i) A is --N═C═O and B is --NHR₆ ',

(ii) A is --NHR₅ ' and B is --N═C═O,

(iii) A is --NR₅ 'COL and B is --NHR₆ ',

(iv) A is --NHR₅ ' and B is --NR₆ 'COL, or

(v) A is halogen and B is --NR₆ 'CONHR₅ ',

wherein R₅ ' and R₆ ' are as defined above and L is a leaving group.Examples of suitable leaving groups L include halogen such as chloro orbromo, imidazole, or phenoxy or phenylthio optionally substituted forexample with halogen.

When A is --N═C═O and B is NHR₆ ' or when A is NHR₅ ' and B is --N═C═Othe reaction is suitably carried out in an inert solvent for exampledichloromethane or toluene at ambient temperature.

When A is --NR₅ 'COL and B is --NHR₆ ' or when A is --NHR₅ ' and B is--NR₆ 'COL, the reaction is suitably carried out in an inert solventsuch as dichloromethane at ambient temperature optionally in thepresence of a base, such as triethylamine or in dimethylformamide atambient or elevated temperature.

When A is halogen and B is --NR₆ 'CONHR₅ ', the reaction is suitablycarried out in an inert solvent such as toluene at elevated temperature,optionally in the presence of a base.

The cyclisation of the compound of formula (IV) to prepare indoles (R₁₀and R₁₁ are a bond) may be effected using standard methodology such asdescribed in Comprehensive Heterocyclic Chemistry 1984 4, 313 et seq. orJ. Het. Chem. 1988 25 p.1 et seq.

Examples of the more important routes include the Leimgruber synthesis,the Fischer synthesis and the Japp-Klingemann variation and the Madelungsynthesis.

Examples of the groups C and D in the preparation of indoles include:

(vi) C is NO₂ and D is CH═CH--NZ₂ where each Z is independently C₁₋₆alkyl or together represent C₂₋₇ alkylene;

(vii) C is NR₁ '--N═C(R₂ ')--CH₂ R₃ ' and D is H;

(viii) C is NH--N═C(CO₂ X)--CH₂ R₃ ' and D is H where X is C₁₋₆ alkyl;and

(ix) C is NR₁ 'COR₂ ' and D is CH₂ R₃ '.

The preparation of indolines includes:

(x) C is NHR₁ ' and D is C(R₃ ')(R₁₁ ')C(R₂ ')(R₁₀ ')L where L is aleaving group.

Indolines may also be prepared by reduction, e.g. with NaCNBH₃, ofindoles produced by variants (vi) to (ix) above.

In reaction variant (vi) (Leimgruber synthesis) the compound of formula(IV) is prepared from the 2-methylnitrophenyl urea by treatment with adialkylacetal of the dialkylformamide OHCNZ₂ with heating and theproduct of formula (IV) cyclised by hydrogenation over a suitablecatalyst such as palladium and charcoal optionally under pressure toyield the compound of formula (I) where R₁ =R₂ =R₃ =H.

In reaction variant (vii) (Fischer synthesis) the compound of formula(IV) is prepared from the hydrazinophenyl urea by dehydration,preferably by heating, with the appropriate ketone R₂ 'COCH₂ R₃ ' andthe product of formula (IV) cyclised by heating with an acid catalystsuch as hydrochloric or sulphuric acid.

In reaction variant (viii) (Japp-Klingemann synthesis) the compound offormula (IV) is prepared from the aminophenyl urea by diazotisationfollowed by treatment for example with CH₃ COCH(CO₂ X)--CH₂ R₃ ' where Xis C₁₋₆ alkyl under basic conditions in aqueous alcohol as solvent.

The product of formula (IV) my then be cyclised as in the Fischersynthesis above.

In reaction variant (ix) (Madelung synthesis) the compound of formula(IV) is cyclised with base in an inert solvent optionally with heating.

In reaction variant (x), the compound of formula (IV) is cyclised byheating in an inert solvent, optionally in the presence of a base.

It will be appreciated that when D is hydrogen, either or both indoleisomers may be formed during the cyclisation process.

Suitable examples of groups R₂ ', R₃ ', R₄ ', and R₇ ' which areconvertible to R₂, R₃, R₄, and R₇ alkyl groups respectively, includeacyl groups which are introduced conventionally and may be converted tothe corresponding alkyl group by conventional reduction, such as usingsodium borohydride in an inert solvent followed by hydrogenolysis in aninert solvent. Hydrogen substituents may be obtained from alkoxycarbonylgroups which may be converted to hydrogen by hydrolysis anddecarboxylation. When R₄ is hydroxy it is preferably protected in thecompound of formula (II) as, for example, benzyl which is removed byhydrogenation.

Suitable examples of a group R₁ ' which is convertible to R₁, includetypical N-protecting groups such as alkoxycarbonyl, in particulart-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl andpara-methoxybenzyl which are converted to R₁ hydrogen using conventionalconditions.

Suitable examples of groups R₅ ' and R₆ ' which are convertible to R₅and R₆ respectively include alkoxycarbonyl and benzyl orpara-methoxybenzyl which are converted to R₅ and/or R₆ hydrogen usingconventional conditions.

Interconversions of R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇ are carriedout by conventional procedures.

For example, in the case wherein R₁, R₂ and R₃ are C₁₋₆ alkyl and R₅ andR₆ are hydrogen it is possible to introduce a C₁₋₆ alkyl group at boththe R₅ and R₆ positions by conventional alkylation using 2 molarequivalents of a C₁₋₆ alkyl halide and 2 molar equivalents of a suitablebase in an inert solvent. Monoalkylation can be achieved using 1 molarequivalent of a C₁₋₆ alkyl halide and base using conventionalconditions. R₁ C₁₋₆ alkyl groups may also be introduced by conventionalalkylation, for example using a C₁₋₆ alkyl halide and base such assodium hydride, or by reduction of C₁₋₆ acyl.

R₄ halo and R₇ halo may be introduced by selective halogenation of thering P or indole/indoline ring respectively using conventionalconditions.

It should be appreciated that it may be necessary to protect any R₁ toR₁₂ hydrogen variables which are not required to be interconverted.

Protection, especially of a R₁ ' hydrogen, may also be necessary duringcoupling reaction (a) and ring-forming reaction (b) above.

Suitable protecting groups and methods for their attachment and removalare conventional in the art of organic chemistry, such as thosedescribed in Greene T. W. `Protective groups in organic synthesis` NewYork, Wiley (1981).

It is preferable, however, to introduce and interconvert the groups R₁to R₁₂ before coupling compounds of formulae (II) and (III) together, orcyclising the compound of formula (IV).

Compounds of formula (I) which are substituted indoles, and theirappropriate derivatives, can be converted to the correspondingindolines, and vice versa, by conventional methods, e.g. reduction withNaCNBH₃ in acetic acid and oxidation using MnO₂ in an inert solvent.

Compounds of formula (II) in which A is NHR₅ ' are known compounds orcan be prepared analogously to known compounds.

For example, aminopyrazine and 4-aminoquinaldine are commerciallyavailable from Aldrich, and 3-amino-6-chloro-pyridazine is commerciallyavailable from Lancaster.

Compounds of formula (II) in which A is --N═C═O may be prepared bytreating a compound of formula (II) in which:

i) A is amino, with phosgene or a phosgene equivalent, in the presenceof excess base in an inert solvent.

ii) A is acylazide (i.e. CON₃), via the nitrene, by thermalrearrangement using conventional conditions (ref L. S. Trifonov et al.,Helv. Chim. Acta 1987 70 262).

iii) A is CONH₂, via the nitrene intermediate using conventionalconditions.

Compounds of formula (II) in which A is --NR₅ 'COL may be prepared byreacting a compound of formula (II) in which A is --NHR₅ ' with phosgeneor a phosgene equivalent, in an inert solvent, at low temperature, ifnecessary in the presence of one equivalent of a base such astriethylamine.

Compounds of formula (II) in which A is halogen and R₄ ' is hydrogen arecommercially available.

Compounds of formula (III) in which B is NHR₆ ' are known compounds orcan be prepared analogously to known compounds, for example by reductionof the corresponding nitroindole or nitroindoline by catalytichydrogenation over Pd/C by the method of P. Fludzinski et al. J. Med.Chem., 1986, 29 2415. Specifically, the compound of formula (III) inwhich R₁ ' and R₂ ' are methyl, R₃ ' is ethyl, R₁₀ ' and R₁₁ ' are abond, R₆ ' and R₇ ' are hydrogen and B is NH₂ is prepared using aprocedure similar to that described by Fludzinski.

The nitroindoles and nitroindolines are commercially available, forexample 5-nitroindole and 5- nitroindoline, or may be preparedconventionally (Comprehensive Heterocyclic Chemistry Vol. 4 p. 313 etseq. (Pergamon Press 1984) and J. Het. Chem. 1988 25 p.1 et seq.)

An R₂ ' alkoxycarbonyl group may be eliminated to give R₂ ' hydrogen,generally under the conditions effecting formation of the nitroindole oras a subsequent step in the process.

R₆ ' alkyl groups may be introduced conventionally, for example byreductive alkylation or acylation and reduction. R₇ ' C₁₋₆ alkyl groupsmay be introduced ortho to a nitro substituent by alkylation using aprocedure similar to that described in G. Bartoli et al., J. Org. Chem.1986 51 3694 and Tetrahedron 1987 43 4221.

Compounds of formula (III) in which B is --N═C═O may be prepared bytreating a compound of formula (III) in which:

i) B is amino, with phosgene or a phosgene equivalent, in the presenceof excess base in an inert solvent.

ii) B is acylazide (i.e. CON₃), via the nitrene, by thermalrearrangement using conventional conditions.

iii) B is CONH₂, via the nitrene intermediate using conventionalconditions.

Compounds of formula (III) in which B is --NR₆ 'COL may be prepared byreacting a compound of formula (III) in which B is --NHR₆ ' withphosgene or a phosgene equivalent, in an inert solvent, at lowtemperature, if necessary in the presence of one equivalent of a basesuch as triethylamine.

Compounds of formula (III) in which B is --NR₆ 'CONHR₅ ' can be preparedfrom the corresponding precursor where B is NHR₆ ' by reaction with anR₅ ' isocyanate under conventional conditions.

Examples of phosgene equivalents include triphosgene,carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate.

Novel intermediates of formula (III) also form part of the invention.

Compounds of formula (IV) may be prepared from the appropriateaminophenyl derivative analogously to compounds of formula (I).

Novel intermediates of formula (IV) also form part of the invention.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

N-oxides may be formed conventionally by reaction with hydrogen peroxideor percarboxylic acids.

Compounds of formula (I) and their pharmaceutically acceptable saltshave 5HT_(1C) receptor antagonist activity and are believed to be ofpotential use in the treatment or prophylaxis of anxiety, depression,migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease,sleep disorders, bullmia, panic attacks, withdrawal from drug abuse suchas cocaine, ethanol, nicone, and benzodiazepines, schizophrenia, andalso disorders associated with spinal trauma and/or head injuries, suchas hydrocephalus.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of anxiety,depression, migraine, anorexia, obsessive compulsive disorders,Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawalfrom drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injuries, such as hydrocephalus.

The invention further provides a method of treatment or prophylaxis ofanxiety, depression, migraine, anorexia, obsessive compulsive disorders,Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawalfrom drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injuries, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment or prophylaxis of anxiety,depression, migraine, anorexia, obsessive compulsive disorders,Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawalfrom drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injuries.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorder will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unitdoses may be administered more than once a day, for example two or threea day, so that the total daily dosage is in the range of about 0.01 to100 mg/kg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention. The following Descriptions illustratethe preparation of intermediates to compounds of the present invention.

Description 1

1-Methyl-5-nitro-1H-indole (D1)

To a stirred suspension of sodium hydride (5.0 g; 167 mmol) indimethylformamide (200 ml) at 0° C. under nitrogen was added5-nitroindole (25 g; 154 mmol) in dimethylformamide. After stirring for0.5 h, iodomethane (10.5 ml; 168 mmol) in dimethylformamide (50 ml) wasadded, and stirring was continued for 2 h. The reaction mixture was thenquenched with water, and poured onto excess water with stirring.Filtration afforded the title compound (27.4 g; 94%).

NMR (CDCl₁₃) δ: 3.88 (3H, s), 6.68 (1H, d, J=3), 7.21 (1H, d, J=3), 7.34(1H, d, J=8, 8.13 (1H, dd, J=8, 2), 8.59 (1H, d, J=2).

Description 2

5-Amino-1-methyl-1H-indole (D2)

A mixture of the nitroindole (D1) (5 g; 28.4 mmol) and 5% palladium oncharcoal in ethanol (300 ml) was hydrogenated at 60 p.s.i. (4.14×10⁵ Pa)at room temperature for 3 h. Removal of the catalyst by filtrationfollowed by evaporation of the solvent gave the title compound (3.39 g,95%).

NMR (CDCl₃) δ: 3.20 (2H, broad s), 3.70 (3H, s), 6.28 (1H, d, J=3), 6.68(1H, dd, J=8, 2), 6.92 (1H, d, J=2), 6.96 (1H, d, J=3), 7.12 (1H, d,J=8).

Description 3

Phenyl N-(1-Methyl-1H-indol-5-yl) carbamate (D3)

To a solution of phenyl chloroformate (2.21 ml; 17.4 mmol) in drytetrahydrofuran (30 ml), cooled in a carbon tetrachloride/solid carbondioxide bath, was added 5-amino-1-methylindole (D2) (2.31 g; 15.8 mmol)followed by triethylamine (2.40 ml; 17.4 mmol). The mixture was stirredfor 45 min at -20° C. (bath temperature), then evaporated. The residuewas dissolved in ethyl acetate, washed with brine, dried and evaporatedto give the title compound (4.29 g; 100%), m.p. 103°-107° C.(EtOAc/petrol).

NMR (CDCl₃) δ: 3.80 (3H, s), 6.45 (1H, d, J=3), 6.93 (1H, broad s), 7.05(1H, d, J=3), 7.25 (5H, m), 7.40 (2H, dd, J=8, 8), 7.74 (1H, broad s).

Description 4

Pyrimidine-5-carboxylic acid (D4)

n-Butyllithium (1.6M in hexane, 6.9 ml, 11 mmol) was added to dry THF(10 ml) and the solution was cooled to -100° C. A solution of5-bromopyrimidine (1.59 g, 10 mmol) in dry THF (50 ml) was added slowly.After 15 min at -80° to -100° C., the mixture was added dropwise ontosolid carbon dioxide in dry THF. After warming to room temperature, themixture was made slightly acidic with dilute sulphuric acid. The solidwas filtered off and extracted with ethanol. The extract was filteredand evaporated and the residue was re-extracted with methanol.Evaporation of solvent gave the title compound (1.48 g, 100%).

NMR (d₄ -MeOH) δ: 9.17 (1H, s), 9.20 (2H, s). m/z (EI): 124 (M⁺)

Example 1

N-(1-Methyl-5-indolyl)-N'-(2-pyrazinyl) urea (E1)

To a suspension of sodium hydride (80% in oil, 0.66 g, 22 mmol) in dryDMF (50 ml) was added 2-aminopyrazine (0.95 g, 10 mmol). After hydrogenevolution had ceased (15 min), phenyl N-(1-methyl-5-indolyl) carbamate(D3) (2.67 g, 10 mmol) was added, followed by a further portion ofsodium hydride (0.2 g). The mixture was stirred overnight at roomtemperature and then evaporated in vacuo. The residue was dissolved indichloromethane/methanol and washed with water and brine. The organicphase was dried and evaporated and the residue was triturated withdichloromethane/petrol. The residue was then recrystallised fromDMSO/water to give the title compound (1.09 g). m.p. 222°-226° C.

Found: C, 62.75; H, 4.83; N, 26.10 C₁₄ H₁₃ N₅ O requires: C, 62.91; H,4.90; N, 26.20% NMR (D₆ -DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.19(1H, dd, J=8, 2), 7.30 (1H, d, J=3), 7.38 (1H, d, J=8), 7.77 (1H, d,J=2), 8.22 (1H, d, J=2), 8.30 (1H, m), 9.01 (1H, s), 9.52 (1H, s), 9.57(1H, s).

Example 2

N-(1-Methyl-5-indolyl)-N'-(3-pyridazinyl) urea (E2)

The title compound (0.53 g) was prepared by the method of Example 1,using sodium hydride (0.59 g, 19.7 mmol), 3-aminopyridazine (0.85 g,8.95 mmol) and carbamate (D3) (2.39 g, 8.95 mmol) in DMF (40 ml). mp.220°-225° C., 96.5% pure by HPLC.

NMR (d₆ -DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18 (1H, dd, J=8,2), 7.30 (1H, d, J=3), 7.39 (1H, d, J=8), 7.72 (1H, dd, J=5, 9), 7.75(1H, d, J=2), 8.0 (1H, d, J=9), 8.85 (1H, d, J=5), 9.69 (1H, s), 9.73(1H, s). m/z (EI): 267 (M⁺), 172, 146.

Example 3

N-(1-Methyl-5-indolyl)-N'-(5-pyrimidinyl) urea (E3)

A mixture of acid (D4, 1.22 g, 9.8 mmol), 5-amino-1-methyl indole (D2,1.43 g, 9.8 mmol), triethylamine (1.4 ml) and diphenylphosphoryl azide(2.1 ml, 10 mmol) in 1,4-dioxan (100 ml) was heated under refluxovernight. The mixture was evaporated and the residue was dissolved indichloromethane and washed with 5% citric acid, sat. sodium bicarbonateand water. The organic phase was dried and evaporated and the residuewas chromatographed on silica (100 g) eluted with 2-15%methanol/dichloromethane. Combination of appropriate fractions followedby recrystallisation from dichloromethane/methanol gave pure (E3, 0.70g). mp 210°-213° C.

Found: C, 62.93; H, 4.84; N, 26.06. C₁₄ H₁₃ N₅ O requires C, 62.91; H,4.90; N, 26.20% NMR (d₆ -DMSO) δ: 3.76 (3H, s), 6.37 (1H, d, J=3), 7.17(1H, dd, J=8, 2), 7.29 (1H, d, J=3), 7.37 (1H, d, J=8), 7.69 (1H, d,J=2), 8.78 (2H, s), 8.91 (3H, s).

Example 4

N-(1-Methyl-5-indolyl)-N'-(4-pyridazinyl) urea (E4)

The title compound was prepared by the method of Example 3, usingpyridazine-4-carboxylic acid (0.5 g, 4 mmol), aminoindole (D2, 0.59 g, 4mmol), triethylamine (0.57 ml) and diphenylphosphoryl azide (0.86 ml,4.1 mmol) in 1,4-dioxan (40 ml). Crude product was chromatographed onsilica (75 g) eluted with 5-10% methanol/dichloromethane. The secondcomponent was extracted with hot methanol to give an insoluble residueof pure title compound (0.11 g). mp 216°-221° C.

Found: C, 62.17; H, 4.85; N, 25.49 C₁₄ H₁₃ N₅ O requires: C, 62.91; H,4.90; N, 26.20% NMR (d₆ -DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18(1H, dd, J=8, 2), 7.30 (1H, d, J=3), 7.38 (1H, d, J=8), 7.70 (1H, d,J=2), 7.81 (1H, dd, J=6, 3), 8.88 (1H, s), 8.91 (1H, d, J=6), 9.20 (1H,d, J=3), 9.29 (1H, s).

Example 5

N-(1-Methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea (E5)

To a suspension of sodium hydride (80% in oil, 0.99 mg, 3.3 mmol in dryDMF (5 ml) was added 5-amino-3-methylisothiazole hydrochloride (0.15 mg,1 mmol). After hydrogen evolution had ceased (15 mln), phenylN-(1-methyl-5-indolyl) carbamate (D3) (0.267 mg, 1 mmol) was added.

The mixture was stirred overnight at room temperature and thenevaporated in vacuo. The residue was dissolved indichloromethane/methanol and the solution was washed with water andbrine, dried and evaporated. The crude product was triturated withdichloromethane/petrol and the residue was chromatographed on silica (10g) eluted with 2% methanol/dichloromethane. Recrystallisation fromdichloromethane/petrol gave the title compound (0.10 g). mp. 186°-189°C., 99.6% pure by HPLC.

NMR (CDCl₃): δ: 2.32 (3H, s), 3.78 (3H, s), 6.32 (1H, s), 6.44 (1H, d,J=3), 7.08 (1H, d, J=3), 7.18 (1H, dd, J=8, 2), 7.27 (1H, d, J=8), 7.64(1H, d, J=2). m/z (EI): 286 (M⁺), 172, 146.

Example 6

N-(1-Methyl-5-indolyl)-N'-(3-methyl-5-isoxazolyl) urea (E6)

The title compound was prepared by the method of Example 5, using5-amino-3-methylisoxazole (0.098 g, 1 mmol), sodium hydride (0.066 g,2.2 mmol) and carbamate (D3, 0.267 g, 1 mmol) in dry DMF (5 ml). Thecrude product was triturated with dichloromethane/petrol, thenrecrystallised from dichloromethane/methanol/petrol to give the titlecompound (0.135 g). mp 186°-189° C., 97.5% pure by HPLC.

NMR (d₆ -DMSO) δ: 2.07 (3H, s), 3.67 (3H, s), 5.84 (1H, s), 6.27 (1H, d,J=3), 7.04 (1H, dd, J=8, 2), 7.18 (1H, d, J=3), 7.26 (1H, d, J=8), 7.58(1H, d, J=2), 8.53 (1H, s). m/z (EI): 270 (M⁺), 172

Example 7

N-(1-Methyl-5-indolyl)-N'-(2-(1,3,4-thiadiazolyl)) urea (E7)

A mixture of 2-amino-1,3,4-thiadiazole (1.01 g, 10 mmol), carbamate (D3,2.67 g, 10 mmol), and N-methylmorpholine (1.2 ml) in DMF (100 ml) washeated at 100°-140° C. overnight, then cooled and evaporated. Theresidue was dissolved in dichloromethane/methanol and washed with brineand water. The organic phase was dried and evaporated, and the residuewas recrystallised from dichloromethane/methanol/petrol to give thetitle compound (1.54 g). mp 217°-220° C. (decomp.).

Found: C, 52.35; H, 4.07; N, 25.29 C₁₂ H₁₁ N₅ OS requires C, 52.73; H,4.06; N, 25.62% NMR (d₆ -DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18(1H, d, J=8), 7.32 (1H, d, J=3), 7.39 (1H, d, J=8), 7.73 (1H, s).

Example 8

N-(1-Methyl-5-indolyl)-N'-(4-(1,2,4-triazolyl)) urea (E8)

To a solution of 1,1'-carbonyldiimidazole (0.27 g) in dichloromethane(10 ml) at 0° C. was added aminomethylindole (D2, 0.22 g, 1.5 mmol) indichloromethane (10 ml). The mixture was stirred at 0° C. for 15 min,then evaporated and the residue was redissolved in dry DMF (10 ml).4-Amino-1,2,4-triazole (0.134 g, 1.6 mmol) was added in DMF (2.5 ml) andthe mixture was heated at 120°-140° C. for 1 h, then poured into water.The aqueous solution was filtered and evaporated to dryness, and theresidue was chromatographed on silica (25 g) eluted with 5-10%methanol/dichloromethane. The second-eluted material was the titlecompound (0.21 g). mp 202°-206° C.

Found: C, 56.36; H, 4.82; N, 32.65 C₁₂ H₁₂ N₆ O requires: C, 56.24; H,4.72; N, 32.79% NMR (d₆ -DMSO) δ: 3.77 (3H, s), 6.35 (1H, d, J=3), 7.18(1H, dd, J=8, 2), 7.29 (1H, d, J=3), 7.35 (1H, d, J=8), 7.65 (1H, d,J=2).

Example 9

N-(1-Methyl-5-indolyl)-N'-(3-quinolyl)-urea hydrochloride (E9)

A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mmol) in drydichloromethane (5 ml) was treated with a solution of5-amino-1-methylindole (D2, 0.29 g, 2 mmol) in dry dichloromethane (5ml).

After 0.25 h, the reaction mixture was evaporated to dryness and theresidue dissolved in DMF (10 ml). 3-Aminoquinoline (0.32 g 2.2 mmol) wasadded and the reaction minute heated to 90° C. for 1 h then cooled andadded to water (200 ml) with vigorous stirring. The precipitate wasfiltered, dried and recrystallised from ethanol affording the product asan off-white solid (0.4 g, 66% yield). This was converted into the titlecompound using HCl in ether. mp 230° C. (from ethanol)

Found: C, 64.42; H, 4.72; N, 15.71. C₁₉ H₁₇ N₄ OCl requires: C, 64.68;H, 4.82; N, 15.87% NMR (d⁶ -DMSO) δ: 3.77 (3H, s), 6.38 (1H, d, J=6),7.2-7.4 (3H, m), 7.77 (3H, m), 8.1 (2H, m), 8.80 (1H, d, J=3), 9.19 (2H,d, J=12), 9.79 (1H, s).

Example 10

N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride (E10)

A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mM) in drydichloromethane (5 ml) was treated with a solution of 5-amino 1-methylindole (D2, 0.29 g, 2 mM) in dry dichloromethane (5 ml). After 0.25 h,the reaction mixture was evaporated to dryness and the residue dissolvedin DMF (10 ml). 6-Aminoquinoline (0.32 g, 2.2 mM) was added and thereaction mixture heated to 90° C. for 1 h then cooled and added to water(200 ml) with vigorous stirring. The precipitate was filtered, dried andrecrystallised from ethanol, affording the product as a white solid(0.32 g, 51%). This was converted into the hydrochloride salt (E2) usingHCl in ether. mp 208° C. (from ethyl acetate).

NMR (d⁶ -DMSO) δ: 3.77 (3H, s), 6.38 (1H, d, J=3), 7.2-7.4 (3H, m),7.7-8.2 (4H, m), 8.48 (1H, s), 8.8-9.1 (3H, m), 9.58 (1H, s). m/z (EI):316 (M⁺, C₁₉ H₁₆ N₄ O)

Example 11

N-(1-Methyl-5-indolyl)-N'-(8-quinolyl) urea (E11)

The title compound was prepared from 8-aminoquinoline, 1, 1'-carbonyldiimidazole and 5-amino-1-methyl-indole (D2) using a procedure similarto that described for Example 10, in 31% yield, m.p. 205°-209° C.

NMR (D₆ -DMSO) δ: 3.76 (3H, s), 6.35 (1H, d, J 3), 7.22 (1H, dd, J 6,2), 7.27 (1H, d, J 3), 7.36 (1H, d, J 6), 7.5-7.54 (2H, m), 7.60-7.65(1H, m), 7.8 (1H, s), 8.39 (1H, d, J 6), 8.57 (1H, m), 8.92 (1H, d, J2), 9.62 (2H, s). Found: M⁺ 316 C₁₉ H₁₆ N₄ O requires 316

Example 12

N-(1-Methyl-5-indolyl)-N'-(5-quinolyl) urea (E12)

The title compound was prepared from 5-aminoquinoline, 1, 1'-carbonyldiimidazole and 5-amino-1-methyl-indole (D2) using a procedure similarto that described for Example 10, in 20% yield, m.p 243°-245° C.

NMR (D₆ -DMSO) δ: 3.76 (3H, s), 6.35 (1H, d, J 2), 7.20 (1H, d, J 6),7.29 (1H, d, J 2), 7.38 (1H, d, J 6), 7.60-7.65 (1H, m), 7.72 (2H, d, J3), 7.77 (1H, s), 8.10 (1H, t, J 2), 8.57 (1H, d, J 6) 8.84 (2H, d, J3), 8.93 (1H, d, J 2) Found: M⁺ 316 C₁₉ H₁₆ N₄ O requires 316

Example 13

N-(1-Methyl-5-indolyl)-N'-(2-methyl-4-quinolyl) urea hydrochloride (E13)

The title compound was prepared from 4-aminoquinaldine, 1,1'-carbonyldiimidazole and 5-amino-1-methyl-indole (D2) using a procedure similarto that described for Example 10 and then converted to the hydrochloridesalt, in 24% overall yield, m.p. 215°-220° C.

NMR (D₆ -DMSO) δ: 2.80 (3H, s), 3.77 (3H, s), 6.39 (1H, d, J 2),7.23-7.33 (2H, m), 7.42 (1H, d, J 6), 7.79-7.84 (2H, m), 8.0-8.11 (2H,dd J 6,6), 8.60 (1H, s), 9.08 (1H, d, J 8), 10.8 (1H, s), 10.92 (1H, s),15.0 (1H, broad s). Found: M⁺ 330 C₂₀ H₁₈ N₄ O requires 330

Example 14

N-(1-methyl-5-indolyl)-N'-(6-isoquinolyl) urea (E14)

The title compound is prepared using standard methodology as describedherein, such as reaction of (D2) with carbonyl diimidazole in a solventsuch as dry dichloromethane, and reacting the product with6-aminoisoquinoline in a solvent such as DMF, with heating.

Example 15

N-(1-Methyl-5-indolyl)-N'-(5-isoquinolyl) urea (E15)

To a solution of carbonyl diimidazole (0.31 g, 2.15 mmol) indichloromethane (20 ml) was added 5-aminosioquinoline (0.25 g, 1.7 mmol)in dichloromethane (20 ml). After stirring at room temperature for 0.5h, the solution was evaporated to dryness. The residue was taken up indimethylformamide (20 ml) and to this solution was added5-amino-1-methyl-indole (D2) (0.25 g, 1.7 mmol) in dimethylformamide (20ml). The reaction mixture was heated to 90° C. for 1 h, then cooled andadded dropwise to water, with vigorous stirring. The resultingsuspension was filtered off, washed with water and dried in vacuo toyield the title compound in 53% yield, m.p. 254°-259° C.

NMR (D₆ -DMSO) δ: 3.77 (3H, s), 6.37 (1H, d, J 3), 7.19 (1H, dd J 6,2),7.28 (1H, d, J 3), 7.37 (1H, d, J 8), 7.65.(1H, t, J 6), 7.75-7.8 (2H,m), 7.99 (1H, d, J 6), 8.32 (1H, d, J 6), 8.57 (1H, d, J 6), 8.84 (2H,d, J 8), 9.29 (1H, s). Found: M⁺ 316 C₁₉ H₁₆ N₄ O requires 316

Example 16

N-(1-Methyl-5-indolyl)-N'-(1-isoquinolyl) urea (E16)

The title compound was prepared from 1-aminoisoquinoline, 1, 1'-carbonyldiimidazole and 5-amino-1-methyl-indole (D2) using a procedure similarto that described for Example 15, in 11% yield, m.p. 230°-233° C.

NMR (CDCl₃) δ: 3.81 (3H, s), 6.47 (1H, d, J 2), 7.07 (1H, d, J 3), 7.30(2H, m), 7.46 (1H, dd J 6,2), 7.61-7.82 (3H, m), 7.97 (1H, s), 8.09-8.16(3H, m), 12.4 (1H, broad s). Found: M⁺ 316 C₁₉ H₁₆ N₄ O requires 316

Example 17

N-(1-Methyl-5-indolyl)-N'-(4-isoquinolyl) urea (E17)

The title compound was prepared from 4-aminoisoquinoline, 1,1'-carbonyldiimidazole and 5-amino-1-methyl-indole using a procedure similar tothat described for Example 1, and then converted to the hydrochloridesalt using hydrogen chloride in ether/ethanol, in 26% overall yield,m.p. 195°-197° C.

NMR (D₆ -DMSO) δ: 3.77 (3H, s), 6.39 (1H, d, J 2), 7.22 (1H, dd J 6,2),7.32 (1H, d, J 3), 7.4 (1H, d, J 6), 7.80 (1H, s), 7.94 (1H, t, J 6),8.13 (1H, t, J 6), 8.39 (1H, d, J 6), 8.55 (1H, d, J 6), 9.24 (1H, s),9.34 (1H, s), 9.50 (2H, d, J 8 ). Found: M⁺ 316 C₁₉ H₁₆ N₄ O requires316

Pharmacological data

[³ H]-mesulergine binding to pig choroid plexus membranes in vitro

Evidence from the literature suggests that 5-HT_(1C) antagonists mayhave a number of therapeutic indications including the treatment ofanxiety, migraine, depression, feeding disorders and obsessivecompulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989)and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46p.542).

The affinity of test drugs for the 5-HT_(1C) binding site can bedetermined by assessing their ability to displace [³ H]-mesulergine from5-HT_(1C) binding sites in pig choroid plexus membranes. The methodemployed was similar to that of Pazos et al., 1984.

Pooled pig choroid plexi were homogenised in 20 vols of Tris HCl buffer(pH7.4) (containing 4mM CaCl₂ and 0.01% ascorbic acid) and centrifugedat 50,000 g for 15 min at 4° C. The supernatant was removed andre-centrifuged. This was repeated a further two times with theincubation of the homogenate (37° C. for 15 min) before the finalcentrifugation. The final pellet was resuspended in 20 vols of bufferand stored at -70° C. until use.

The tissue suspension (50 ml) was incubated with [³ H]-mesulergine (2nM) in Tris HCl buffer (pH7.4) at 37° C. (containing 0.01% ascorbicacid, 4 mM CaCl₂) and 3×10⁻⁸ M spiperone for 30 minutes. Non-specificbinding was measured in the presence of mianserin (10⁻⁶ M). Sixconcentrations of test drug (10⁻⁹ to 10⁻⁴ M final concentration) wereadded in a volume of 50 ml. The total assay volume was 500 ml.Incubation was stopped by rapid filtration using a Skatron cellharvester and radioactivity measured by liquid scintillationspectrometry. The IC₅₀ values were determined and the pK_(i) (thenegative logarithm of the inhibition constant) calculated from the ChengPrusoff equation where ##EQU1## K_(i) =inhibition constant.C=concentration of [³ H]-mesulergine

Kd=Affinity of mesulergine for 5-HT_(1C) binding sites.

Curzon, G. A. and Keanett, G. A. (1990). TIPS, Vol. 11, 181-182.

Fozard, J. R. and Gray, J. A. (1989). TIPS, Vol. 10, 307-309.

Pazos, A. et al. (1984). Eur. J. Pharmacol., 106, 531-538.

[³ H]-Mesulergine binding to rat HT_(1C) clones expressed in 293 cellsin vitro

The affinity of test drugs for the 5-HT_(1C) binding site can bedetermined by assessing their ability to displace [³ H]-mesulergine from5-HT_(1C) clones expressed in 293 cells (Julius et al., 1988). Themethod employed was similar to that of Pazos et al., 1984.

The cells suspension (50 μl) was incubated with [³ H]-mesulergine (0.5nM) in Tris HCl buffer (pH 7.4) at 37° C. for 30 minutes. Non-specificbinding was measured in the presence of mianserin (10⁻⁶ M). Tenconcentrations of test drug (3×10⁻⁹ to 10⁻⁴ M final concentration) wereadded in a volume of 50 μl. The total assay volume was 500 μl.Incubation was stopped by rapid filtration using a Brandel cellharvester and radioactivity measured by scintillation counting. The IC₅₀values were determined using a four parameter logistic program (DeLean1978) and the pK_(i) (the negative logarithm of the inhibition constant)calculated from the Cheng+Prusoff equation.

Julius et al. (1988) Science 241, 558-564.

DeLean A, Munson P. J., Rodbaud D. (1978) Am. J. Physiol. 235, E97-E102.

The compounds of examples 3-7, 12, 13, 15 and 17 have pK_(i) values inthe range 5.97 to 8.3.

Reversal of MCPP-induced Hypolocomotion

Administration of m-(chlorophenyl)piperazine (mCPP) to rats induceshypolocomotion (Kennett and Curzon 1988, Luckie et al. 1989) as seenwith the related drug 1-(m-trifluoromethylphenyl)piperazine (TFMPP)(Lucki and Frazer 1982, Kennett and Curzon 1988). This effect wasblocked by the non specific 5-HT_(1C) /5-HT₂ receptor antagonistsmianserin, cyproheptadine and metergoline and perhaps by mesulergine. Itwas not blocked by the 5-HT₂ receptor antagonists ketanserin andritanserin at relevant doses (Kennett and Curzon 1991) nor byantagonists of 5-HT_(1A), 5-HT_(1B), 5-HT₃, α₂ adrenoceptors ordompamine D₂ receptors. The effect of mCPP is therefore considered to bemediated by 5-HT_(1C) receptors (Kennett and Curzon 1988) as confirmedby subsequent studies (Lucki et al., 1989). Since mCPP causeshypolocomotion when infused into the cerebral ventricles this effect isprobably centrally mediated (Kennett and Curzon 1988).

mCPP-induced hypolocomotion was measured in automated locomotion cagesof dimensions 56 cm long×161/2× cm wide×25 cm high and made of blackperspex. Two photobeams traversed the width of the cages at either endat ground level. Sequential breaking of these beams allowed themeasurement of cage transits.

Male Sprague Dawley rats (200-250 g) (Charles River) were housed ingroups of six. They were given drugs orally 1 h pretest and 40 minslater mCPP (7 mg/kg i.p.). After a further 20 min they were placed inindividual automated cages in groups of four under red light in anadjacent room. After 10 min the test was terminated. Reversal ofmCPP-induced hypolocomotion was considered as evidence of in vivocentral 5-HT_(1C) receptor antagonist properties.

Kennett, G. A., Curzon, G., (1988). Brit. J. Pharmacol. 94, 137-147.

Kennet G. A., Curzon, G., (1991). Brit. J. Pharmacol. 103, 2016-2020.

Lucki, I., Frazer, A., (1982) Am. Soc. Neurosci. 8(abstr.), 101.

Lucki, I., Ward, M. R., Frazer, A., (1989). J.Pharmacol. Exp. Therap.249, 155-164.

The compound of Examples 2 and 3 had ID₅₀ values of 47.0 and 43.7 mg/kgp.o.

Rat Fundus: 5-HT_(1C) -like Receptors Introduction

The 5-HT receptor in the rat fundic strip (RFS) has been characterisedas `5-HT_(1C) -like` as its pharmacology is similar, but not identical,to that of rat 5-HT_(1C) receptor dones. Hence this tissue may be usedto assess the 5-HT_(1C) -like antagonist properties of compounds.

Methods

Whole stomachs were obtained from male CD Rats (Charles River, 250-350g). Strips of fundus (2 cm×0.5 cm) were cut from the greater curvatureand the mucesae carefully removed. Tissues were then further dissectedinto smaller strips (2 mm×20 mm) which were mounted in organ bathscontaining oxygensted Tyrodes solution at 37° C. containing indomethacin(3 μM). Preparations were maintained under a resting tension of 0.5 gand exposed to the irreversible MAO inhibitor pargyline (100 μM for 30minutes followed by washout). Over a 1 h equilibration period, ratfundic strips were challenged with 1×10⁻⁸ M 5-HT at 15 minute intervalsuntil constant responses were obtained. Fifteen minutes later, acomplete cumulative concentration-effect curve to the standard agonist5-HT (1×10⁻¹⁰ upwards) was constructed to determine the individualsensitivity of each preparation. A further concentration-effect curve toeither 5-HT, or other agonists was constructed no sooner than 1 h aftercompletion of the previous curve. When necessary tissues wereequilibrated with the antagonists over this one hour period. Antagonistsaffinities are expressed as pA₂ estimates.

Results

The compound of Example 5 had a pA₂ value of 7.9.

We claim:
 1. A compound of formula (I) or a salt thereof: ##STR6##wherein: P represents a quinoline or isoquinoline residue;R₁ is hydrogenor C₁₋₆ alkyl; R₂, R₃, R₁₀ and R₁₁ are independently hydrogen or C₁₋₆alkyl, or R₁₀ and R₁₁ together form a bond, or R₂ and R₁₀ or R₃ and R₁₁together form a C₂₋₆ alkylene chain; R₄ is hydrogen, C₁₋₆ alkyl,halogen, NR₈ R₉, OR₁₂ or COOR₁₂, where R₈, R₉ and R₁₂ are independentlyhydrogen or C₁₋₆ alkyl; R₅ and R₆ are independently hydrogen or C₁₋₆alkyl; and R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; andwherein the urea moiety is attached at the 4-, 5- or 6-position of theindole or indoline ring, provided that P is not pyridyl when R₁₀ and R₁₁form a bond.
 2. A compound according to claim 1 in which R₁ is methyl.3. A compound according to claim 2 in which R₂ and R₃ are hydrogen.
 4. Acompound according to claim 3 in which R₁₀ and R₁₁ are both hydrogen orR₁₀ and R₁₁ together form a bond to form an indole structure.
 5. Acompound according to claim 4 in which R₄, R₅, R₆ and R₇ are hydrogen.6. A compound according to claim 1 in which the urea moiety is attachedat the 5-position of the indole or indoline ring.
 7. A compoundaccording to claim 1 which is selectedfromN-(1-methyl-5-indolyl)-N'-(3-quinolyl)-urea,N-(1-methyl-5-indolyl)-N'-(6-quinolyl)-urea,N-(1-methyl-5-indolyl)-N'-(8-quinolyl)urea,N-(1-methyl-5-indolyl)-N'-(5-quinolyl)urea,N-(1-methyl-5-indolyl)-N'-(2-methyl-4-quinolyl)urea,N-(1-methyl-5-indolyl)-N'-(6-Isoquinolyl)urea,N-(1-methyl-5-indolyl)-N'-(5-isoquinolyl)urea,N-(1-methyl-5-indolyl)-N'-(1-isoquinolyl)urea,N-(1-Methyl-5-indolyl)-N'-(4-isoquinolyl)urea,or a pharmaceuticallyacceptable salt thereof.
 8. A pharmaceutical composition which comprisesa compound according to claim 1 and a pharmaceutically acceptablecarrier or excipient.
 9. A method of antagonizing 5HT_(1C) receptor byadministering to a subject in need of such treatment an effective amountof a compound according to claim 1.